key: cord-0918465-9nwtnptf
authors: Novak, Natalija; Cabanillas, Beatriz
title: Viruses and asthma: the role of common respiratory viruses in asthma and its potential meaning for SARS‐CoV‐2
date: 2020-07-20
journal: Immunology
DOI: 10.1111/imm.13240
sha: 0916f5db2db8fc74fa8da81e46b10ace34128376
doc_id: 918465
cord_uid: 9nwtnptf

Viral infections and atopic diseases are closely related and contribute to each other. The physiological deficiencies and immune mechanisms that underlie atopic diseases can result in a suboptimal defense against multiple viruses and promote a suitable environment for their proliferation and dissemination. Viral infections, on the other hand, can induce per se several immunological mechanisms involved in allergic inflammation capable to promote the initiation or exacerbation of atopic diseases such as atopic asthma. In a world that is affected more and more by factors that significantly impact the prevalence of atopic diseases, coronavirus disease 2019 (COVID‐19) induced by the novel coronavirus severe acute respiratory syndrome (SARS‐CoV‐2) is having an unprecedented impact with still unpredictable consequences. Therefore, it is of crucial importance to revise the available scientific literature regarding the association between common respiratory viruses and asthma, as well as the newly emerging data about the molecular mechanisms of SARS‐CoV‐2 infection and its possible relation with asthma, to better understand the interrelation between common viruses and asthma and its potential meaning on the current global pandemic of COVID‐19.

Certain atopic diseases such as atopic asthma or atopic dermatitis (AD) have evolved into diseases with higher susceptibility to infections with microorganisms that commonly affect the respiratory system or the skin, respectively. The characteristic CD4 T helper 2 (Th2) polarization that differentiates atopic patients from non-atopic individuals can impair the ability to mount an effective immune response against viruses. In that respect, Th2 cytokines have been described to be permissive to microbial invasion due to their inhibitory function on epithelial barrier proteins, cell-mediated immunity, antimicrobial proteins, or type I interferon production, which are the first lines of defense against viruses. [1] [2] [3] [4] In this context, it has been demonstrated that a high proportion of asthmatic patients and individuals with AD complicated by eczema herpeticum (ADEH) have a predisposition to induce a lower production of type I interferons, decreasing in this way the defense against viral infections. 3, 5, 6 In line with these observations, an inhibitory effect of Th2 inflammation on the induction of type I interferon, through different mechanisms such as crossregulation of the high-affinity receptor for IgE (FcεRI) and toll-like receptors (TLRs), inhibition of TLRs by Th2 cytokines, or overexpression of suppressors of cytokine signaling. 7-10 Furthermore, the allergic inflammation that characterizes atopic asthma is marked by the infiltration of different immune cells that have the potential to interact with respiratory viruses with an impact on viral infection and asthma exacerbation. 11, 12 Additionally, data from different studies have revealed that in a background of atopy, IgEmediated reactivity against certain respiratory viruses such as respiratory syncytial virus (RSV) and human rhinovirus (RV) might exist. Although the function of IgE against viruses is still not clear, it has been suggested that it may have a role in the exacerbation of asthma induced by respiratory viruses. 13, 14 In ADEH, IgE against viruses such as herpes simplex virus 1 has also been described. 15 Therefore, there is abundant scientific evidence that indicates that all the aforementioned factors can synergistically contribute to a deficient response to viruses and promote viral dissemination in target organs.

On the other hand, it has been demonstrated that certain viral infections can induce per se the activation of immunological mechanisms and morphological changes such as tissue remodeling that can contribute to the initiation or aggravation of atopic diseases. In line with this assumption,

This article is protected by copyright. All rights reserved several studies have revealed that epithelial cells infected by specific viruses can induce the production of pro-Th2 cytokines such as IL-25 and IL-33, activating group 2 innate lymphoid cells (ILC2s), dendritic cells (DCs), and Th2 cells, increasing in that way Th2 inflammatory pathways that are linked to allergic inflammation. 16, 17 In that respect, meta-analyses demonstrated that severe respiratory viral infections that require hospitalization early in life are associated with an increased risk of asthma development later in life. 18, 19 In the pandemic of COVID-19 induced by the novel coronavirus SARS-CoV-2, efforts have been made to find potential risk factors. Although the first scientific evidence seems to indicate that allergic asthma is not a strong risk factor for an increased severe infection of SARS-CoV-2, several studies have started to explore at a molecular and cellular level the relation between COVID-19 and asthma. 20, 21, 22, 23 Yet, little is known regarding the potential consequences and sequelae that SARS-CoV-2 infection can produce since such infection is characterized by a strong hyperinflammation and tissue remodeling. For that reason, it is crucial to review the available scientific literature that explores respiratory viruses and their consequences such as the initiation or exacerbation of asthma, as well as the scientific knowledge that is emerging regarding COVID-

In this review, we intend to carry out an in-depth overview of the current scientific insights about the interconnection between viruses that commonly infect the airways and allergic asthma and to provide an update of the data regarding the molecular mechanisms of SARS-CoV-2 infection and its possible relation with asthma.

The pathophysiology of asthma is characterized by airway inflammation, hyperreactivity, and airway remodeling that can lead to a decrease in lung function due to the narrowing of the airways.

In the specific case of atopic asthma, there is a predominance of Th2 cells and ILC2s that produce type 2 cytokines involved in allergic inflammation which is implicated in the initiation and exacerbation of asthmatic processes. 24 However, Th2 immunity alone cannot explain the large pathophysiological events that orchestrate during asthma exacerbation. In that respect, there is

This article is protected by copyright. All rights reserved growing scientific evidence that viral infections of the respiratory tract, especially the ones produced by single-stranded RNA viruses, are associated with asthma, particularly in the pediatric population, although also in adult patients. 25 The association between respiratory viruses and asthma has been analyzed during years from two different perspectives. On one hand, a branch of research has focused on the impact that respiratory viral infections have on the development and/or the exacerbation of asthma. On the other hand, a wide spectrum of scientific research has focused on the study of asthma as a risk factor for the development of repeated and severe respiratory viral infections due to the physiological deficiencies and immune mechanisms that underlie the disease.

RSV and RV belonging to Paramyxoviradae and Picornaviradae family respectively are singlestranded RNA viruses involved in the infectious processes of the human respiratory tract. They are the respiratory viruses that have been more commonly associated with the development of asthma or asthma exacerbation. Other viruses such as influenza virus also seem to have an impact on asthma, while coronavirus, adenovirus, parainfluenza virus, metapneumovirus, or bocaviruses have been described as a potential risk factor for asthma exacerbations although at a lower extend. 26, 27 The first scientific evidence that associated respiratory viral infections and asthma development or exacerbation came from human epidemiologic studies in the early seventies especially carried out in pediatric populations. Subsequent experimental studies using human samples and animal models started to explore the mechanisms involved in such association. Data from epidemiologic studies have shown that most children under the age of 2 years have been infected at least once with RSV, which is a highly contagious virus that produces infections that in most cases cause mild symptomatology. However, around 2-3% of the patients infected with RSV have severe symptoms for which hospitalization is needed. 28 Early studies in the seventies and eighties started to suggest an association between RSV infection and the development of asthma. 29, 30 In the following years, several other studies supported this hypothesis. In this context, a meta-analysis carried out in 2013 examined 15 studies performed from 1978 to 2012 that included 82,008 pediatric individuals in whom the association between hospitalization due to infection of the lower

This article is protected by copyright. All rights reserved respiratory tract produced by RSV in the first three years of life and the risk of asthma development was studied. The meta-analysis showed that 21.9% of the pediatric patients hospitalized for RSV infection developed asthma as a sequela during the first five years of life. It was also estimated that from the total of asthmatic children under the age of five years, the ones that had been infected by RSV requiring hospitalization represent 6.4%. Although the metaanalysis showed a strong association between RSV hospitalization in the first years of life and the development of asthma, follow-up studies demonstrated that such a connection was reduced by age over time. 19 However, this observation was challenged by further systemic reviews that found a continued substantial risk of asthma in adulthood in those patients hospitalized for RSV infection early in life. Such risk was in part due to a late onset of asthma that may not be analyzed in all the follow-up studies. Differences in the definition of asthma among the studies could also be responsible for such discrepancies. 31 RV has also been identified as one of the respiratory viruses mainly associated with acute asthma development and/or exacerbations. Based on its genetics, RV can be classified in species RV-A, -B, and -C which are composed of more than 160 types. Typically, RV is associated with infection of the upper respiratory tract although scientific evidence has shown that the lower tract can also be a target for RV. The connection between RV infection and the development of asthma has been analyzed in several epidemiologic studies. A meta-analysis carried out in 2017 included 15 studies that involved pediatric patients under the age of three years that were diagnosed with wheezing associated with RV infection and had a follow-up study to evaluate the development of asthma.

The meta-analysis revealed that there was an association between RV wheezing diagnosed in the 3 first years of life and an increased risk of development of asthma later in life. Interestingly, such association was still significant with increased age (≥10 years). 18 The clinical association between respiratory viral infections and asthma can also be analyzed from the perspective of the predisposition that an asthmatic background has for the development of a higher number and/or more severe viral infections in the airways. In that respect, data from several clinical studies have revealed that atopic pediatric patients may have a higher risk of adverse responses to respiratory viral infections, such as the ones produced by RV, and those infections are significantly related with wheezing in children that were hospitalized due to asthma. 32, 33 In young adults have also been found that an asthmatic background with high levels of total IgE seems to be predisposed to exacerbated responses to acute infections with viruses such as RV. 34

This article is protected by copyright. All rights reserved Besides RV and RSV, other respiratory viruses such as influenza virus, coronaviruses, parainfluenza virus, adenovirus, or metapneumovirus might be associated with asthma initiation or exacerbation. 26, 35 However, although previous studies have found that certain strains of coronaviruses can be associated with asthma exacerbation, this link seems to be weaker than for other respiratory viruses such as RV or RSV. 36, 37 In the case of COVID-19 induced by the novel coronavirus SARS-CoV-2, a single-stranded RNA virus, the symptoms can range from fever, cough, and shortness of breath to severe pneumonia that can compromise lung function requiring mechanical ventilation. 38 Although the true mortality rate of COVID-19 is still currently difficult to estimate, the first data given by the World Health Organization considering the crude mortality ration (reported deaths divided by reported cases) situated the figure between 3-6%. 39 Risk factors such as advanced age, hypertension, respiratory disease, cardiovascular disease, diabetes, male sex, or high levels of lactate dehydrogenase have been associated with severe COVID-19. 40, 41 Obesity has also been pointed out as a risk factor. 42, 43 The first scientific evidence seems to indicate that asthma does not seem to constitute a risk factor for an enhanced infection or an aggravation of COVID-19. 44 Two studies that have analyzed the prevalence of asthma in two cohorts of COVID-19 patients in Wuhan, China, have established such prevalence in 0 -0.9 %. 41, 45 These results were further confirmed in study populations from other countries. 46 However, recent data from a large cohort of patients in the USA demonstrated that asthma was significantly linked to a longer duration of the intubation in patients with COVID-19 younger than 65. 47 In a prospective study carried out in the United Kingdom it was found that the prevalence of asthma in 605 COVID-19 patients was 17.9%, which is greater than the prevalence found in the general population. 48 These data suggest that asthma may be a greater risk factor for COVID-19 than previously suggested. 49, 50 In this context, different research groups have begun to analyze at a molecular and cellular level the relation of asthma and COVID-19. Very recent studies have shown that Th2 cytokines have a role in the modulation of the entry receptor of SARS-CoV-2, angiotensin-converting enzyme-2 (ACE2) in the airways and transmembrane protease, serine 2 (TMPRSS2), the host protease that facilitates the binding of SARS-CoV-2 to its receptor. Studies found that the expression of TMPRSS2 in the airway epithelium was greatly upregulated by Th2 cytokines, especially by IL-13, however, the same Th2 cytokines decreased the levels of ACE2 in nasal and bronchial

This article is protected by copyright. All rights reserved epithelium. Respiratory allergy was also linked to a significant decrease in the expression of ACE2. 20,21,22 23 Interestingly, in a large cohort of asthmatic patients in the USA, it was found that the expression of ACE2 and TMPRSS2 was specifically increased in sputum cells of males, African Americans individuals, and patients suffering from diabetes mellitus. 51 From these results, it seems that Th2 cytokines have differential effects on two key proteins involved in the infective mechanisms of SARS-CoV-2. Moreover, an asthmatic background seems to modulate these two proteins differently depending on the group of patients in question (male versus female or African Americans versus Caucasians). However, and attending to the so-far reported cases of asthma among COVID-19 patients, the globally available data seems to indicate that Th2 inflammation linked to atopic asthma may not have a strong implication in a severe course of the disease. 20, 21, 22, 23 Despite these facts, SARS-CoV-2 is a new coronavirus that infects humans and little information is available regarding the possible outcomes derived from SARS-CoV-2 infection in humans and the potential effects on the initiation or exacerbation of diseases such as asthma. It is known that the most severe form of COVID-19 seems to be linked to a 'cytokine storm' leading to a hyperinflammation that can induce severe injuries in the lungs in a way that the disease, in the cases that overcome it, can produce important sequelae in multiple organs or tracts, such as the respiratory tract. 52, 53 In the following sections, we will focus on the available scientific knowledge regarding the molecular mechanisms that underlie the association between respiratory viruses that normally infect humans such as RV, RSV, influenza virus, and asthma. These findings could give important insights and directions about the potential impact that SARS-CoV-2 can have on patients who are currently suffering from this infection. In the bidirectional and probably interconnected association between respiratory viruses, such as RV, RSV, influenza virus, and asthma, multiple molecular and cellular mechanisms have been described that could explain the interrelation between them. These mechanisms will be described in the following sections, differentiating, on the one hand, the mechanisms involved in the impact that viral infections can potentially have on the initiation or exacerbation of asthma (section 2.2), and on the other hand, the mechanisms that could explain why an asthmatic phenotype seems to be more likely to suffer from infections produced by respiratory viruses (section 2.3).

This article is protected by copyright. All rights reserved

Different mechanisms have been suggested to be involved in the initiation or exacerbation of asthma as a consequence of respiratory viral infections. Although the severity and the outcomes of a respiratory viral infection depend on factors such as the host immune system or environmental aspects, it has been observed that respiratory viral infections can induce per se immunological changes and morphological alterations that can contribute to the initiation or aggravation of asthmatic processes (Figure 1 ). Infections produced by respiratory viruses such as RSV or RV are characterized by airways inflammation and tissue remodeling that could have an impact on the initiation of asthmatic processes.

The epithelial barrier in the airways is the first place for viral replication and propagation, which can seriously alter its integrity and homeostasis and derive in the release of pro-inflammatory cytokines and increased allergen sensitization. In that respect, several studies have revealed that epithelial cells infected by respiratory viruses can promote the production of cytokines such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) activating ILC2s, DCs, and Th2 cells, increasing Th2 inflammatory pathways linked to allergic inflammation. 16, 17, 54 (Figure 1 ). Support for this assumption comes from observations gained in mouse models in which cytokines derived from the airway epithelium such as IL-25, IL-33, and TSLP were produced rapidly upon viral infections with respiratory viruses such as RV or RSV. The epithelial-derived cytokines production went along with an augmented number of ILC2s, which are important producers of IL-13, deriving in allergic inflammation. The blockade of IL-25, IL-33, TSLP, or their receptors in neonatal mice exposed to respiratory viruses, decreased Th2 allergic inflammation, hyperresponsiveness of the airways, eosinophilia, and mucus production. 55, 56 In that sense, the

This article is protected by copyright. All rights reserved induction of ILC2s through IL-25, IL-33, and TSLP during RSV and RV infection has been found to be key for RSV and RV-induced asthma. IL-13-producing ILC2s during respiratory viral infections are an indicator of the severity of the disease. [54] [55] [56] [57] Additional cytokines and compounds with regulatory effect over ILC2s activation have been described during cell injury associated with respiratory viral infections. In that respect, during RSV infection, an increase in the production of IL-1β, a regulator of ILC2s, has been observed with a potential role in the initiation of asthma. 58 Uric acid is also produced during cell injury associated with RSV infection. This compound induced the production of reactive oxygen species and the activation of the NLRP3 inflammasome, with an effect on IL-1β production and consequent ILC2s activation. Uric acid has been associated with pulmonary injury and asthma. Inhibition of uric acid or IL-1β in murine models of RSV infection reduced the production of mucus, infiltration of ILC2s, type 2 immune response, and development of asthma during RSV infection and allergen challenges, which highlight their importance in virus-induced asthma. 59

In the initiation of asthma other immune mechanisms besides or in a combination with type 2 inflammation can take place, such as neutrophilic inflammation in which Th1 and Th17 cells play an important role. In this context, it has been observed that asthma can be initiated by respiratory viruses by the activation of immune mechanisms different from the ones involved in type 2 inflammation, although they can also act in combination with this type of inflammation. In that respect, in a mouse model of virus-induced asthma, the signaling of IL-1β has been implicated in neutrophilic inflammation. 60 IL-17, a proinflammatory cytokine produced by Th17 cells, which is known to contribute to asthma by the induction of lung inflammation, mucus production, and promotion of Th2 responses, has been found to be augmented during RSV infections and to play a key role in the pathogenesis of asthma induced by RSV. 61 Other studies have confirmed that Th17 and Th2 pathways seem to be implicated in the response to RSV infection, which can derive in persistent type 2 immunity implicated in asthma. [61] [62] [63] [64] 

This article is protected by copyright. All rights reserved Respiratory viruses can also have an impact on asthma development due to their interaction with different immune cells. Epithelial cells infected by respiratory viruses such as RV produce inflammatory factors that promote chemotaxis, proliferation, and activation of specific immune cells, amplifying in that way inflammatory processes. Although it was previously suggested that RV is not able to infect immune cells, recent studies have argued against this concept and have demonstrated that RV can infect macrophages, 65 T cells 66, 67 or mast cells (MCs) which can act as viral reservoirs and release viral particles contributing in that way to viral infection. 11 Due to the proximity of infiltrated inflammatory immune cells with the epithelium from the upper and lower airways, it is reasonable to expect that those cells have also a role in RV infection with a potential impact in asthma initiation or exacerbation. In that respect, a study showed that RV interacted with CD19+ B cells, CD4+ T cells, CD8+ t cells, and monocytes in vitro. RV was able to be internalized by CD19+ B cells, to induce their proliferation, and to form viral replication centers in which the newly released virions were able to infect other cells (Figure 1 ). Using PBMCs it was found that RV induced their activation and production of inflammatory cytokines such as IL-6, TNF-α, IFN-α, IFN-γ, IL-27, MIP-1β, IL-1β, and RANTES. 68

The compositions of the microbiota in the upper and lower respiratory tracts (URT and LRT) has been found to show similarities, however, they differ in a way that the density of microorganisms tends to be higher in the URT than in the LRT in healthy individuals. Data from different studies have shown that asthmatic patients have an increase in the population of different microbial communities in the lungs with an enrichment in the abundance of specific species. 69, 70 Interestingly, infections by respiratory viruses also have a relevant impact on the airway microbiota. In that respect, it has been found that respiratory viruses can modify the composition of the airway microbiota in a sense that can promote the growth of pathogens that can affect not only the URT but also the LRT with a potential impact on asthma exacerbation. In this context, it has been demonstrated that certain respiratory viruses can increase the adherence of pathogenic bacteria to the lung epithelium with a promotion of their entrance into the LRT leading to potential secondary bacterial infections. 71, 72 The infections produced by respiratory viruses can also alter the

This article is protected by copyright. All rights reserved innate immunity against bacteria, impairing its clearance. 73 The relation of respiratory viruses and airway microbiota has been shown to be reciprocal and ample scientific evidence has demonstrated that airway microbiota can also alter the course of viral infections through the influence that it exerts on the host immune responses. In that respect, data from animal models have shown that commensal microbiome in the URT has a protective function against the airway hyperresponsiveness induced by RSV, and the use of antibiotics that decreases specific populations in the URT microbiome reverts this effect. 74 The same effect has also been found for other respiratory viruses. 75 Respiratory viruses can also compromise the structural integrity of the epithelial barrier during their infective processes. In that respect, the replication of certain respiratory viruses in epithelial cells can induce loss of ciliated cells which derives in morphological damages that can promote airway hyperresponsiveness and aggravation of asthmatic processes. 76, 77 Apoptotic mechanisms in the epithelial barrier induced in the host, which initially has the function of limiting viral spreading, can cause further damage to the structure of the airway epithelium. Scientific evidence has also shown that respiratory viruses can disrupt tight junctions in the epithelium, disturbing cell-to-cell connections with an increase in paracellular permeability. 78, 79 Furthermore, certain respiratory viruses also have the capacity to interfere with processes of repair and wound healing in the airway epithelium which can further alter the integrity and homeostasis of the epithelial barrier . 80

This article is protected by copyright. All rights reserved Asthma as a risk factor for respiratory viral infections: mechanisms involved As has been already mentioned, asthma pathophysiology is complex and several of the mechanisms that underlie the disease have been pointed out as facilitators of the spreading and infection of respiratory viruses with an impact on asthma exacerbations. In that context, the predominant Th2 inflammation which is a hallmark of atopic asthma and it is characterized by Th2 cytokines IL-4, IL-5, and IL-13 produced by Th2 cells and ILC2s, has been associated with impaired protection against viruses. Th2 inflammation constitutes an immune response that is not involved in the immune defense against viruses. Not only it is a response that is not involved in virus protection, but also, Th2 inflammation can promote the inhibition of different mechanisms involved in the protection against viruses 81 ( Figure 2) . Furthermore, the characteristic airway inflammation, bronchial obstruction, and hyperresponsiveness that underlie asthmatic processes represent a suitable environment for the widespread of specific respiratory viruses.

Type I interferons (IFN-α/IFN-β) are antiviral cytokines that constitute the first line of defense against viruses. They are induced upon ligation of viral components to pattern recognition receptors (PRRs) expressed in different cell types. An extensive body of scientific evidence has demonstrated that a high proportion of asthmatic patients has a predisposition to produce lower levels of type I interferons upon respiratory viral infections, decreasing in that way the defense against viral infections. 5,6 Such impairment has been suggested to depend on the specific site of the respiratory tract, with higher impact on cells from the lower airways, and on the different stages of asthma or its phenotypes, with opposite effect (overproduction of type I interferons) in specific asthmatic phases or phenotypes. 82, 83 The impairment may also depend on the specific respiratory virus that infects the airways. 83 However, attending to the findings of numerous studies, it seems to be clear that in at least a subgroup of patients with asthma, an impairment of type I interferon production exists with a specific role in increased viral load, infection severity, and perpetuation of Th2 inflammation due to lack of the counterregulation effect of type I interferons. 81, 84, 85 Considerable research has been done to elucidate the mechanisms involved in the deficient production of interferons in a subgroup of asthmatic patients. The association of

This article is protected by copyright. All rights reserved allergen exposure and a lower expression of type I interferons has been suggested. In this context a cross-regulation mechanism between the high-affinity receptor for IgE (FcεRI) and TLRs in certain cell types such as plasmacytoid dendritic cells (pDCs) has been described, that may explain why the crosslinking of IgE bound to FcεRI by allergens may result in a reduced TLR expression and ultimately in a decreased capacity to secrete type I interferons for viral defense 7 (Figure 2) . Furthermore, the concept of a deficient production of type I interferons in asthmatic patients associated with an inhibitory effect of the IgE cross-linking in pDCs has been further analyzed. A recent study found that PBMCs and pDCs from pediatric patients with exacerbated asthma increased the production of IFN-α in the presence of Omalizumab (an anti-IgE antibody) when they were cultured with RV, influenza virus, and with IgE cross-linking. Omalizumab also decreased the expression of FcεR1α on pDCs and such a decrease was linked with a lower exacerbation of asthma. 86 Using human bronchial epithelial cells (HBECs) and a mouse model of asthma exacerbation, it was found that the exposure to house dust mite (HDM) before viral infection led to a decreased interferon response in HBECs and the mouse model of asthma. Such impaired response was mediated by the direct effect of HDM on the signaling pathway of TLR3, which suggests that allergens can impact on PRRs and their normal antiviral function. 87 Other components involve in Th2 inflammation such as the Th2 cytokines IL-4 and IL-5 have also been implicated in the inhibition of TLR3 expression and its signaling through interferon-responsive factor 3, which decreased type I interferons in response to RV. 8 All these findings suggest that Th2 inflammation characteristic for allergic asthma has an inhibitory effect on the induction of type I interferons production. Another interesting connection between asthma and a lower type I interferon production arises from studies that analyzed the expression of suppressor of cytokine signaling 1 (SOCS1), a regulator that negatively controls type I and type II interferon production.

The expression of SOCS1 can be induced by Th2 cytokines and specific respiratory viruses.

SOCS1 was found to be increased in epithelium from the bronchi of asthmatics and its expression seemed to be linked to asthma severity. In HBECs obtained from asthmatic individuals and infected with RV, an increased expression of SOCS1 accompanied by interferon deficiency and enhanced RV replication were found. 9,10 SOCS1 had a direct role in the suppression of interferons production upon RV infection in a mouse model. 9

This article is protected by copyright. All rights reserved

The exposure to allergens in the airways of asthmatic patients induce alterations in the epithelium that promote an increase of pro-Th2 epithelial-derived cytokines. Data from different studies have demonstrated that these epithelial-derived cytokines in asthma synergistically interact with respiratory viruses to perpetuate allergic inflammation and to promote asthma exacerbations 88 ( Figure 2) . That is the case of the epithelial cytokine IL-33 which is involved in the initiation of allergic inflammation upon allergen encounter in atopic individuals. Recently it has been demonstrated that the major local sources of IL-33 during asthma exacerbations in the presence of influenza virus were bronchial ciliated cells in patients with mild asthma. The study found that IL-33 in contrast to TSLP suppressed the expression of IFN-β in DCs and epithelial cells, having IL-33 inhibitory action on innate as well as on adaptive immunity against influenza virus, which increased viral load and viral spread. Consequently, IL-33 produced increased hyperresponsiveness of the airways and allergic inflammation. 89 Similar results were found using a Pneumovirus in a mouse model of asthma induced by cockroach extract. 90 In the case of RV, it has been observed that IL-33 together to IL-4, IL-5, and IL-13 were induced in the airways of asthmatic patients during RV infection but not in healthy individuals that were also exposed to RV. In asthmatic patients, there was a correlation between IL-33 levels and IL-5, IL-13, and viral load. 16 In line with this observation, it has been found that IL-33 exposure to human circulating leukocytes incubated with RV increased IL-5 and IL-13 production by leukocytes from asthmatic patients but not from healthy individuals. IL-33 also increased ST2 surface expression, which is the IL-33 receptor, in asthmatic patients but not in healthy subjects, being ST2+ innate lymphoid cells the cell types involved in the increased release of IL-13. In that way, IL-33 and respiratory viruses such as RV seem to interact in a synergistically way in asthmatic patients with a potential contribution to asthma exacerbations. 91 Interestingly, the chronic expression of IL-33 in epithelial cells from asthmatic patients was associated with a decreased antiviral response against RV together to an increased RV-induced exacerbation. The study also found that the blockade of IL-33 reduced type 2 inflammation, viral load, and promoted antiviral responses in a preclinical mouse model of chronic asthma and RV infection. The use of anti-IL-33 antibody also produced a decrease in RV replication and increased antiviral cytokines in human airway epithelial cells (AECs) from asthmatic patients. 92

This article is protected by copyright. All rights reserved

Allergic inflammation that underlies atopic asthma is characterized by the infiltration of different immune cells that can interact with respiratory viruses with a potential impact on viral infection and/or asthma exacerbation (Figure 2 ). In that respect, it is known that MCs numbers are increased in asthmatic patients. MCs can also be found in the bronchial epithelium of asthmatics during experimental RV infection. 93 Data from a study that utilized human MC line LAD2 and primary human cord blood-derived MCs revealed that MCs mounted an innate response upon RV infection, however, and despite this fact, MCs were permissive for the replication of RV and they were able to release viral particles, acting as a reservoir for RV which can potentially contribute to asthma exacerbation induced by RV. 11 Eosinophils are another cell type that have a proinflammatory role in asthmatic processes since they produce cytotoxic compounds and reactive oxygen species that contribute to tissue damage. It has been observed that during viral infections in asthmatic patients, eosinophils tend to accumulate in the airways, which is also of hallmark in atopic and nonatopic asthma. A recent study found that RSV and influenza viruses can adhere to human eosinophils and are inactivated after their internalization by eosinophils. Interestingly, eosinophils from asthmatic patients showed an impaired capacity to interact and capture viral particles compared to eosinophils from healthy controls, and this reduced capacity correlated with asthmatic severity. The reduced antiviral function of eosinophils in asthmatic patients during respiratory viral infections could contribute to virus-induced asthma exacerbations. 12 In line with this observation, it has been shown that the frequency of M1-like macrophages, which are involved in anti-viral responses through type I and III interferon production, were decreased in asthmatic patients during asthma exacerbation induced by RV. 94 These results seem to indicate that several immune cells that normally have an antiviral function in healthy individuals are found in lower frequency in asthmatic patients or with an altered functionality, thus promoting respiratory viral infection with detrimental consequences for asthmatic symptoms.

This article is protected by copyright. All rights reserved Another mechanism that connects atopy and viral infection is based on the fact that in a background of atopy, specific IgE against certain viruses can be produced and although its function is not exactly known, it has been suggested that antiviral IgE could have a possible link with the exacerbation of allergic asthma. 95, 96 The phenotype of allergic asthma, characterized by a greater Th2 polarization and relative Th1 deficiency, may promote the production of IgE against respiratory viruses (Figure 2 ). In that respect, studies in mice have demonstrated that specific IgE against respiratory viruses such as RSV can be produced and they have an important role in the increase of Th2 inflammation in the lungs and exaggerated responsiveness in the airways. 97, 98 That anti-viral IgE may constitute a maladaptive immune response against respiratory viruses that would circumvent classical viral immune-protective responses with a possible promotion of disseminated viral infection in the airways. In this context, it has been demonstrated in human studies that IgE against RSV is made as part of the antiviral response to RSV infection and the levels of IgE anti-RSV were found to be higher in asthmatic subjects compared with nonasthmatic individuals. 13 Another study found IgE against RV in the sera of subjects who have been exposed to them. 14 Therefore, there is growing evidence that antiviral IgE produced as part of an antiviral immune response may contribute to the exacerbation or even development of atopic diseases although further studies in human samples should be carried out to support this hypothesis. 14

Many of the mechanisms that underlie asthma not only have a detrimental effect on the airways of asthmatic patients but can also decrease or block an adequate immune response to viral respiratory infections. This effect might lead to an aggravation of the asthmatic status. This is the case of infections caused by RSV, RV, or influenza virus. Interestingly, the first scientific evidence indicates that an asthmatic phenotype does not appear to be a strong risk factor for an increased severe infection with the new coronavirus SARS-CoV-2. However, little is known about the effects and sequelae that the infection caused by SARS-CoV-2 can produce in the lung function of patients who have overcome the disease. In this review, it has been detailed that certain respiratory viral infections can induce per se immunological changes and morphological alterations that can

This article is protected by copyright. All rights reserved contribute to the initiation or aggravation of asthmatic processes. For that reason, during the pandemic caused by COVID-19, that is impacting the world in a way rarely seen before and which is characterized by lung damage, 'cytokine storm' and hyperinflammation, it is of vital importance to monitor and exhaustively evaluate the consequences and sequelae that COVID-19 can produce in the patients who went through the disease. In the context of Th2 polarization in atopic asthma high amounts of specific IgE against different

Atopic dermatitis

Atopic dermatitis and filaggrin

Risk factors of atopic dermatitis patients for eczema herpeticum

Atopic dermorespiratory syndrome is a correlate of eczema herpeticum

Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children

Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus

Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells

Accepted Article This article is protected by copyright. All rights reserved

Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells

Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons

Transforming growth factor-beta promotes rhinovirus replication in bronchial epithelial cells by suppressing the innate immune response

IgE anti-respiratory syncytial virus antibodies detected in serum of pediatric patients with asthma

Accepted Article This article is protected by copyright. All rights reserved

Rhinovirus specific IgE can be detected in human sera

IgE reactivity against herpes simplex virus 1 in patients with atopic dermatitis complicated by eczema herpeticum

IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo

Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation

Association between rhinovirus wheezing illness and the development of childhood asthma: a meta-analysis

Association between respiratory syncytial virus hospitalizations in infants and respiratory sequelae: systematic review and meta-analysis

Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium

Association of Respiratory Allergy, Asthma and Expression of the SARS-CoV-2 Receptor, ACE2

Type 2 Inflammation Modulates ACE2 and TMPRSS2 in Airway Epithelial Cells

TMPRSS2 and furin gene expression in the airways of people with asthmaimplications for COVID-19

Role of viral infections in the development and exacerbation of asthma in children

Prevalence of viral respiratory tract infections in children with asthma

Accepted Article This article is protected by copyright. All rights reserved

Molecular characterization and distinguishing features of a novel human rhinovirus (HRV) C, HRVC-QCE, detected in children with fever, cough and wheeze during

Review of epidemiology and clinical risk factors for severe respiratory syncytial virus (RSV) infection

Cell-mediated immune response to respiratory syncytial virus infection: relationship to the development of reactive airway disease

Wheezing, asthma, and pulmonary dysfunction 10 years after infection with respiratory syncytial virus in infancy

Elevated risk of asthma after hospitalization for respiratory syncytial virus infection in infancy

Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing

Asthma exacerbations in children associated with rhinovirus but not human metapneumovirus infection

Accepted Article This article is protected by copyright. All rights reserved

Experimental rhinovirus challenges in adults with mild asthma: response to infection in relation to IgE

Virus-induced exacerbations in asthma and COPD

Update on Human Rhinovirus and Coronavirus Infections

Regional, age and respiratory-secretion-specific prevalence of respiratory viruses associated with asthma exacerbation: a literature review

A Novel Coronavirus from Patients with Pneumonia in China

World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report -46

Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: A systematic review and meta-analysis

Accepted Article This article is protected by copyright. All rights reserved

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Clinical findings of patients with coronavirus disease 2019 in Jiangsu Province, China: a retrospective, multi-center study

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Asthma and COVID-19: is asthma a risk factor for severe outcomes?

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

Allergy and asthma in children and adolescents during the COVID outbreak: what we know and how we could prevent allergy and asthma flares?

Asthma prolongs intubation in COVID-19

Associations with COVID-19 hospitalisation amongst 406,793 adults: the UK Biobank prospective cohort study

The OpenSAFELY Collaborative. OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients

Update on asthma prevalence in severe COVID-19 patients

COVID-19 Related Genes in Sputum Cells in Asthma: Relationship to Demographic Features and Corticosteroids

HLH Across Speciality Collaboration UK. COVID-19: consider cytokine storm syndromes and immunosuppression

In the eye of the COVID-19 cytokine storm

The Innate Cytokines IL-25, IL-33, and TSLP Cooperate in the Induction of Type 2 Innate Lymphoid Cell Accepted Article This article is protected by copyright. All rights reserved Expansion and Mucous Metaplasia in Rhinovirus-Infected Immature Mice

Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33

Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells

Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin

Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus-Induced Immune Responses

Inhibition of uric acid or IL-1β ameliorates respiratory syncytial virus immunopathology and development of asthma

IL-1β mediates lung neutrophilia and IL-33 expression in a mouse model of viral-induced asthma exacerbation

Accepted Article This article is protected by copyright. All rights reserved

IL-17-induced pulmonary pathogenesis during respiratory viral infection and exacerbation of allergic disease

Sexassociated TSLP-induced immune alterations following early-life RSV infection leads to enhanced allergic disease

Respiratory syncytial virus infection in the absence of STAT 1 results in airway dysfunction, airway mucus, and augmented IL-17 levels

Respiratory virusinduced TLR7 activation controls IL-17-associated increased mucus via IL-23 regulation

Rhinovirus replication in human macrophages induces NF-kappaB-dependent tumor necrosis factor alpha production

Rhinovirus has the unique ability to directly activate human T cells in vitro

Accepted Article This article is protected by copyright. All rights reserved

Rhinovirus inhibits IL-17A and the downstream immune responses in allergic asthma

Human rhinoviruses enter and induce proliferation of B lymphocytes

Application of a neutral community model to assess structuring of the human lung microbiome

Respiratory microbiota: addressing clinical questions, informing clinical practice

Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species-and cell type-dependent manner

Rhinovirus enhances various bacterial adhesions to nasal epithelial cells simultaneously

Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection

Accepted Article This article is protected by copyright. All rights reserved

Pharyngeal microflora disruption by antibiotics promotes airway hyperresponsiveness after respiratory syncytial virus infection

Bacterial colonization dampens influenzamediated acute lung injury via induction of M2 alveolar macrophages

From bronchoconstriction to airways inflammation and remodeling

Rhinoviruses in the pathogenesis of asthma: the bronchial epithelium as a major disease target

Effects of human rhinovirus on epithelial barrier integrity and function in children with asthma

Respiratory syncytial virus infection influences tight junction integrity

Rhinovirus infection induces cytotoxicity and delays wound healing in bronchial epithelial cells

Accepted Article This article is protected by copyright. All rights reserved

Viral infections in allergy and immunology: How allergic inflammation influences viral infections and illness

Interferon response to respiratory syncytial virus by bronchial epithelium from children with asthma is inversely correlated with pulmonary function

Interferon response and respiratory virus control are preserved in bronchial epithelial cells in asthma

Bronchial mucosal IFN-α/β and pattern recognition receptor expression in patients with experimental rhinovirus-induced asthma exacerbations

Impaired innate interferon induction in severe therapy resistant atopic asthmatic children

Enhanced plasmacytoid dendritic cell antiviral responses after omalizumab

Accepted Article This article is protected by copyright. All rights reserved

House dust mite impairs antiviral response in asthma exacerbation models through its effects on TLR3

Impaired airway epithelial cell responses from children with asthma to rhinoviral infection

IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral immunity

Aeroallergen-induced IL-33 predisposes to respiratory virus-induced asthma by dampening antiviral immunity

Interleukin 33 Selectively Augments Rhinovirus-Induced Type 2 Immune Responses in Asthmatic but not

Chronic IL-33 expression predisposes to virus-induced asthma exacerbations by increasing type 2 inflammation and dampening antiviral immunity

M1-like macrophages are potent producers of anti-viral interferons and M1-associated marker-positive lung macrophages are decreased during rhinovirus-induced asthma exacerbations

Immunoglobulin E, what is it good for?

The role of viruses in the development and exacerbation of atopic disease

Virus-specific IgE enhances airway responsiveness on reinfection with respiratory syncytial virus in newborn mice

The role of virus-specific immunoglobulin E in airway hyperresponsiveness

Accepted Article This article is protected by copyright. All rights reserved

The authors declare no competing interests.

This article is protected by copyright. All rights reserved